Amino Acids

, Volume 44, Issue 2, pp 701–713

Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket

  • Yu Bai
  • Huifang Xue
  • Kun Wang
  • Lifeng Cai
  • Jiayin Qiu
  • Shuangyu Bi
  • Luhua Lai
  • Maosheng Cheng
  • Shuwen Liu
  • Keliang Liu
Original Article

Abstract

Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell–cell fusion and infection.

Keywords

HIV-1 Gp41 Peptide Six-helix bundle Covalent inhibitor 

Supplementary material

726_2012_1394_MOESM1_ESM.doc (2.6 mb)
Supplementary material 1 (DOC 2667 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Yu Bai
    • 1
  • Huifang Xue
    • 1
    • 2
  • Kun Wang
    • 1
  • Lifeng Cai
    • 1
  • Jiayin Qiu
    • 3
  • Shuangyu Bi
    • 4
  • Luhua Lai
    • 4
  • Maosheng Cheng
    • 2
  • Shuwen Liu
    • 3
  • Keliang Liu
    • 1
  1. 1.Beijing Institute of Pharmacology and ToxicologyBeijingChina
  2. 2.Key Laboratory of Structure Based Drugs Design and Discovery of Ministry of EducationShenyang Pharmaceutical UniversityShenyangChina
  3. 3.School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouChina
  4. 4.Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Structural Chemistry for Unstable and Stable Species, College of Chemistry and Molecular EngineeringPeking UniversityBeijingChina

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